Extended release compositions comprising as active compound venlafaxine hydrochloride

ABSTRACT

The present invention relates to an extended release composition comprising as active compound Venlafaxine Hydrochloride, in which Venlafaxine Hydrochloride is coated on a non pareil inert core, which coated core is then coated with polymeric layer which enables the controlled release of the Venlafaxine Hydrochloride.

The present invention relates to extended release compositionscomprising as active compound venlafaxine hydrochloride.

Venlafaxine hydrochloride is an antidepressant having formula (1)

being designated(R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl)-ethyl]cyclohexanolhydrochloride or (±)-1-[a](dimethylamino)-methyl]p-methoxybenzylcyclohexanol hydrochloride, having the empirical formula of C₁₇H₂₇NO₂hydrochloride and molecular weight of 313.87.

Venlafaxine hydrochloride is a white to off-white crystalline solid witha solubility of 572 mg/ml in water (adjustment to ionic strength of 0.2M with sodium chloride). Its octanol:water (0.2 M sodium chloride)partition coefficient 0.43. EFFEXOR XR, the Brand product, is formulatedas an extended release capsule for once-a-day oral administration.

The drug release has so far been controlled by diffusion through thecoating membrane on the spheroids and is not pH-dependent. Knowncapsules containing venlafaxine hydrochloride comprise amountsequivalent to 37.5 mg, 75 mg, or 150 mg of venlafaxine. The inactiveingredients are mainly cellulose, ethylcellulose, gelatin,hydroxypropylmethylcellulose, iron oxide, and titanium dioxide.

Controlled or extended release dosage forms of medicament areconventionally produced as hydrogel matrix-based tablets. With thistechnology, the controlled release dosage forms are simply prepared bymixing the active material with the appropriate rate of controllingpolymers and then that mixture is compressed into the desired controlledrelease tablets. The rate-controlling polymers are normally termed ashydrogels. Examples of such polymers are cellulose ethers such as ethylcellulose or hydroxypropylcellulose. Patents describing preparationmethods of such dosage forms are described, for example, in US PatentSpecifications 4,966,768 and 4,389,393.

In some cases, for example with very water soluble active materials andwith relatively high doses, it is not feasible to produce tablets whichenable appropriate control on the drug's release. This is the case, forexample with venlafaxine hydrochloride.

In such a case, a suitable approach is encapsulating the drug andproducing extended release capsule dosage forms. When preparation ofsuch dosage forms is considered, the preferred way is to mix the activeingredient with at least one binding agent to form a uniform mixturewhich is later moistened with water or with an appropriate organicsolvent to form an extrudable plastic mass, from which small particles,cylindrical in shape (1 mm diameter), of drug/matrix are extruded,chopped into appropriate lengths and converted to spheroids usingspheronization equipment. These spheroids are further dried and thenfilm-coated with an appropriate polymer to form a film with the desiredrelease patterns. The most widely used excipient in the extrudingprocess is microcrystalline cellulose in its different grades; usually,water is used for the wetting process.

Polymers widely used for coating are ethyl cellulose or EUDRAGIT(ammonio methacrylate copolymer, type A or B). Water-soluble ingredientsare normally mixed with the ethyl cellulose or with other hydrophobicpolymers, such as pore forming agents, to assist the control on thedrug's release through the hydrophobic coating layer. The water-solubleingredients, such as hydroxypropylcellulose or polyethylene glycol, mayserve as plasticizers as well.

Venlafaxine hydrochloride has so far been formulated into a controlledrelease dosage form with the ability to provide in a single dose atherapeutic blood serum level of the drug over a twenty four hourperiod. By this method, tighter plasma therapeutic range control can beobtained and multiple dosing is avoided in this manner. The sharp peaksand troughs in blood plasma drug levels are avoided as well.

With the conventional release dosage forms of venlafaxine hydrochloride(tablets), peak blood plasma levels appeared after 2-4 hrs, in contrastto the extended release dosage forms, when plasma levels of venlafaxinehydrochloride rose after administration for between five to eight hrs(average−6) and then begin to fall through a protracted, substantiallylinear decrease from the peak plasma level for the reminder of theperiod, maintaining therapeutic level of the drug during the entiretwenty four hours period.

In WO 99/22724 (AHP, Sherman), a detailed description of preparing anencapsulated dosage form (coated spheroids) of venlafaxine hydrochlorideis provided. By the method described therein, a spheroid core isprepared by extruding and spheronizing a mixture of the drug withmicrocrystalline cellulose, and then coating it with an ethyl cellulosehydroxypropylcellulose mixture.

This dosage form provides an extended release product with the followingin vitro dissolution specifications:

Time (hrs) Average % venlafaxine HCL release 2 <30 4 30-55 8 55-80 1265-90 24 >80

These dissolution characteristics are pH- and RPM-independent.

In the present invention, an alternative once daily bioequivalentformulation to the innovator's one (EFFEXOR XR, described in WO99/22724) has been developed.

As already mentioned, with high dose water-soluble product, such asvenlafaxine hydrochloride (150 mg), the usual preferred way ofencapsulating it is by preparing and coating appropriate beads, usingthe extrusion spheronization process.

In the present invention, the microencapsulation has been changed, i.e.,is being performed by layering the drug over an inert nonpareil core,and then coating it with an appropriate polymeric mixture.

The present invention thus consists in an extended release compositioncomprising as active compound venlafaxine hydrochloride, in whichvenlafaxine hydrochloride is coated on a nonpareil inert core, whichcoated core is then coated with a polymeric layer which enables thecontrolled release of the venlafaxine hydrochloride.

The composition preferably comprises 30-60% of venlafaxine hydrochlorideper weight of the total dosage form.

In a preferred embodiment of the present invention, the venlafaxinehydrochloride is suitably connected to a binder; said binder may be,e.g., polyvinylpyrrolidone (povidone), hydroxypropylcellulose,hydroxypropylmethylcellulose, etc. The composition preferably comprises0.5%-10% of the binder per weight of the total dosage form.

Advantageously the nonpareil inert core is an inert sugar core, amicrocrystalline cellulose, or the like. The composition preferablycomprises 30-60% of the core per weight of the total dosage form.

Alternatively, the drug might be sprayed as it is and the water is thenused as binding enhancement agent.

Advantageously, the coated core is coated with anisolating/protecting/separating layer, which layer is suitably composedof polymers such as polyvinylpyrrolidone, hydroxypropylcellulose,hydroxypropylmethylcellulose, microcrystalline cellulose, carrageenan,GMS, etc. The composition preferably comprises 0.5-10% of the isolatinglayer per weight of the total dosage form.

The core or the isolating layer is coated then with an additionalpolymeric layer which enables the controlled release of venlafaxinehydrochloride. Said additional polymeric layer is composed, e.g., of ahydrophobic polymer mixed with an appropriate hydrophobic or hydrophilicplasticizer. Said polymeric layer is suitably sprayed over the coatednonpareil layer or over the isolating layer.

Appropriate coating polymers are, e.g. EUDRAGIT, cellulose derivativessuch as hydroxypropylmethylcellulose, ethyl cellulose, celluloseacetate, etc. Their suitable plasticizers are, e.g., castor oil, dibutylsebacate, glyceryl monostearate, diethyl phthalate, glyceryltriheptanoate, triethylcitrate, etc.

The coating polymeric layer may also be a wax-based coating.

The composition preferably comprises 2-15% of the hydrophobic polymerper weight of the total dosage form, and preferably 0.1-2% per weight ofthe hydrophobic plasticizer per weight of the total dosage form.

The above processes are conventional processes that may be performed ina fluidized bed coater with a bottom spraying mechanism.

In the composition according to the present invention, preferably notmore than 40% of the drug is released after two hours, not more than 60%released after 4 hours, and not more than 80% after 8 hours.

The compositions obtained are suitably, e.g., filled into hard gelatincapsules or compressed into tablets.

This formulation has an identical in vitro dissolution profile asEFFEXOR XR (see Sherman, WO99/22724). They are not sensitive to anychanges in dissolution conditions. It is bioequivalent to EFFEXOR XR 150mg caps.

The coating process being used to produce the composition according tothe present invention is more efficient than the method being used inthe Sherman patent. Moreover, it enables the preparation of the drug ina single type of equipment, e.g. a fluidized bed coater.

The present invention will now be illustrated with reference to thefollowing examples, without being limited by them.

The process for preparing the composition according to the presentinvention is suitably performed as follows (all temperatures are givenin degrees centigrade):

-   -   a. When venlafaxine hydrochloride is connected to a binder the        venlafaxine hydrochloride is connected to the binder by methods        known per se.    -   b. Stage 1        -   Coating the nonpareil core with the venlafaxine            hydrochloride (advantageously connected with a binder) is            performed at an inlet temperature of 45-55° (preferably at            50°) at an outlet temperature of 35-45° (preferably at 40°).        -   At the end of the spraying process, the composition is dried            for 10 minutes without nozzle with 30 cfm air flow.    -   c. Stage 2        -   The coated core obtained in Stage 1 is coated with the            insulating layer at an inlet temperature of 60°+/−3° at an            outlet temperature of 50°+/−2°.    -   d. Stage 3 (when an insulating layer is present in Stage 2)        -   The core is coated with a further preliminary layer; the            conditions of said coating are:

Inlet temp: 50° +/− 2° Outlet temp: 40° +/− 5°

EXAMPLE NO. 1 Without Binder

Stage 1: Components Nonpareils 25/30 150 gr Venlafaxine hydrochloride37.5 gr H₂O 150 gr. Stage 2: Components - 150 gr layered pellets fromstage 1 ETHOCEL 45 cp 15 gr METHOCEL 5 cp 1 gr Ethanol BP 300 gr

-   -   At the end of the spray process the composition is dried for 10        minutes without nozzle with 30 cfm.

EXAMPLE NO. 2

Stage 1: components Nonpareils (inert sugar pellets) 150 gr PovidoneK-30 3.3 gr. Venlafaxine hydrochloride 165 gr. Ethanol BP 670 gr. Stage2: components - 150 gr. layered pellets from stage 1 ETHOCEL 45 cp 15 grMETHOCEL 5 cp 1 gr Ethanol BP 300 gr

-   -   The coating process was performed in a “4” fluidized bed coater        made by Coating Place Inc. USA.

EXAMPLE NO. 3

Stage 1: components Nonpareils 25/30 150 gr Venlafaxine hydrochloride37.5 gr Povidone K-30 0.75 gr Ethanol BP 160 gr Stage 2: components -150 gr layered pellets from stage 1 EUDRAGIT RS 30 D 150 gr Triethylcitrate 9 gr Glycerol monostearate 2.25 gr Polysorbate 80 1 gr Water 140gr

-   -   The coating process was performed in a “4” fluidized bed coater,        made by Coating Place Inc. USA.

EXAMPLE NO. 4

Stage 1: components Nonpareils 25/30 150 gr. Povidone K-30 0.75 gr.Venlafaxine-HCL 37.5 gr. Ethanol-BP 160 gr. Stage 2: components - 150gr. layered pellets from stage 1 EUDRAGIT RS 30 D 150 gr. EUDRAGIT RL 30D 15 gr. Triethyl citrate 9 gr. Glycerol monostearate 2.25 gr.Polysorbate 80 1 gr Water 140 gr.

-   -   All processes were performed in a “4” fluidized bed coater, made        by Coating Place Inc. USA.

EXAMPLE NO. 5

Stage 1: components - 150 gr. Nonpareils 25/30 Povidene K-90 4.5 gr.Venlafaxine-HCL 150 gr. Ethanol BP 670 gr. Water 110 gr Stage 2:components - 150 gr. pellets from stage 1 Povidone K-30 3.75 gr.Ethanol-absolute 60 gr. Stage 3: components - 150 gr. Pellets from stage2 ETHOCEL 100 cp 8 gr. Dibutyl sebacate 0.8 gr. Ethanol-absolute 300 gr.

In the above examples, EUDRAGIT RS 30 D is poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride)1:2:0.1.EUDRAGIT RL 30 D is poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.2.ETHOCEL is ethyl cellulose and METHOCEL is methyl cellulose.

1. A pH-independent extended release dosage form having specifieddissolution characteristics, comprising: venlafaxine hydrochloride in anamount of 30-60% based on the total weight of the dosage form; saidvenlafaxine hydrochloride being coated on a nonpareil inert core, saidnonpareil inert core comprising 30-60% based on the total weight of thedosage form; the venlafaxine hydrochloride being optionally connected toa binder in a binder amount of 0.5-10% based on the total weight of thedosage form wherein said binder, when present, is selected from thegroup consisting of polyvinylpyrrolidone, hydroxypropylcellulose andhydroxypropylmethylcellulose; an isolating layer coating saidvenlafaxine hydrochloride and comprising 0.5-10% based on the totalweight of the dosage form, said isolating layer beingpolyvinylpyrrolidone; and a controlled release layer coated over saidisolating layer, said controlled release layer comprising a controlledrelease polymer mixed with a plasticizer, said controlled releasepolymer comprising 2-15% based on the total weight of the dosage form,said controlled release polymer being ethyl cellulose, and saidplasticizer comprising 0.1-2% based on the total weight of the dosageform, said plasticizer being dibutyl sebacate; the parameters beingselected so as to control release of the venlafaxine hydrochloride overan approximately 24 hour period in a manner that the following pH andrpm independent in vitro dissolution specifications are obtained: Time(hrs) Average % venlafaxine HCl release 2 <30 4 30-55 8 55-80 12 65-9024 >80.


2. In a method for administering venlafaxine hydrochloride to a patientin need thereof, comprising administering the venlafaxine hydrochlorideas an extended release composition to the patient, the improvementwherein the extended release composition is in accordance with claim 1.